tbuckley/cabot-search huggingface dataset:
DIPG-62. Reducing the levels of genomic 5-hydroxymethylcytosine by inhibiting the TET pathway induces apoptosis and decreases proliferation in Diffuse Intrinsic Pontine Glioma (DIPG)
Authors: Akhila Parthasarathy, Antje Arnold, Charles Eberhart, Eric Raabe
Journal: Neuro-Oncology (2022)

Abstract The H3K27M mutation, observed in 70%-90% of DIPG, causes global hypomethylation. The Ten-Eleven-Translocation enzymes, TETs, which convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) regulate the methylation patterns in the genome. Previously, we observed an increase in the 5hmC levels and altered TET activity in DIPG. We hypothesize that targeting the TETs in DIPG could restore the epigenetic balance. In this study, we target the TET pathway with cell-permeable 2-hydroxyglutarate (2HG) and Bobcat339, a cytosine-based TET inhibitor. We see a dose-dependent decrease in 5hmC (46-96% reduction) and increase in 5mC (~5fold increase) in multiple DIPG cell lines treated with 2HG. We see a corresponding increase in apoptosis and reduction in proliferation (~8fold increase in cleaved-Caspase3 signal (P=0.0001) and ~55% reduction in BrdU-incorporation measured by IF (P=0.0036) in JHH DIPG16A with similar results in JHH DIPG1, HSJD007, and SUDIPG6). We see a 54-90% reduction in 5hmC and ~3fold increase in 5mC with Bobcat 339 treatment in DIPG cell lines JHH DIPG1, JHH DIPG16A, HSJD007, and SUDIPG6. We also see a corresponding increase in apoptosis as measured by cleaved PARP western blot and decrease in proliferation as measured by BrdU incorporation (approximately 32-53% decrease in proliferation). Combined treatment with 2HG and Bobcat339 lead to greater decreases in 5hmC and increases in 5mC compared to single treatment, with synergistic suppression of cell growth as measured by SynergyFinder in HSJD007, JHH DIPG1, and JHH DIPG16A. In vivo studies targeting DIPG orthotopic xenografts are currently underway. These results suggest that TETs contribute to the hypomethylated state observed in DIPG. Thus, inhibiting the TETs can be explored as a potential therapeutic approach to treat DIPG.
Clinical and surgical predictors of urinary tract endometriosis after primary surgical treatment: A single high-volume centre experience
Authors: L. Lambertini, F. Di Maida, A.A. Grosso, R. Tellini, F. Valastro, A. Cadenar, S. Nardoni, A. Tuccio, A. Mari, F. Petraglia, L. Masieri, A. Minervini
Journal: European Urology (2022)
Exploring the value of intraoperative frozen section in the diagnosis and treatment of patients with early-stage ovarian cancer: A retrospective analysis of 421 patients.
Authors: Jinghong Chen, Zhaolin Gong, Mengpei Zhang, Rutie Yin
Journal: Journal of Clinical Oncology (2022)

e17568 Background: Rapid and accurate judgment of the source and nature of tumors is conducive for surgeons to select the appropriate scope and method of surgery, and avoid unnecessary over-treatment or under-treatment. This study aimed to explore the diagnostic and treatment value of intraoperative frozen section pathology in patients with early-stage ovarian cancer (EOC) in the real world. Methods: We retrospectively collected the clinical and pathological data of EOC at West China Second University Hospital between January,2013 and December,2017, which diagnosed as stage ⅠA- IIA EOC according to the International Federation of Gynecology and Obstetrics (FIGO) 2014 standard of Ovarian cancer, fallopian tube cancer and peritoneal cancer. Results: There were totally 421 cases of EOC in the Second West China Hospital of Sichuan University from 2013 to 2017. The average age was 42.9 ± 13.5 years old. There were 395 patients who had finished the comprehensive staging surgeries. Group A consisted of 239 patients (60.5%) who had completed staging operation through only one surgery, while Group B consisted of 156 cases (39.5%) who had completed that through a second-time surgery. The frozen section submission rate of staging operation in the two groups were 99.2% (237/239) and 35.3% (55/156), respectively. Meanwhile, the coincidence rates of frozen and paraffin sections in the two groups were 98.3% (233/237) and 70.9% (39/55). The submission rate and coincidence rate of intraoperative frozen sections in Group A were higher than those in Group B (the submission rate: X 2 = 199.983, P&lt; 0.05; the coincidence rate: X 2 = 52.541, P &lt; 0.05). Conclusions: Our results confirm that increasing the submission rate of intraoperative frozen section and improving the accuracy of frozen section attach great importance to the diagnosis and treatment of EOC. Once identified, timely and comprehensive staging surgery can help improve patient outcomes for those who do not take fertility preservation into consideration.[Table: see text]
NSAB C-14: CORRECT-MRD II—Second colorectal cancer clinical validation study to predict recurrence using a circulating tumor DNA assay to detect minimal residual disease.
Authors: Mohamed E. Salem, Shannon Leigh Huggins-Puhalla, Thomas J. George, Carmen Joseph Allegra, Melanie R. Palomares, Frederick L Baehner, Norman Wolmark
Journal: Journal of Clinical Oncology (2022)

TPS3632 Background: Patients (pts) with stage II and III colon cancer (CC) have unique post-operative decisions regarding adjuvant chemotherapy (ACT). There is a subset of stage II pts with defined clinicopathologic features associated with poor prognosis who may benefit from ACT, although more discriminating and objective predictors of benefit are needed. In addition, there may be a subset of Stage III CC pts who could tolerate a de-escalation of ACT or who may require intensification of ACT to improve clinical outcome. Detectable ctDNA after resection of early-stage solid tumors has been associated with very high risk of recurrence, suggesting ctDNA is evidence of minimal residual disease (MRD). Several studies are ongoing to investigate the role of ctDNA in the optimal management of pts with CC using different assay technologies. Methods: This is a prospective, observational, multicenter study in the United States and Canada of 750 pts who have undergone complete surgical resection for stage II or III CC, have FFPE tissue available from the primary resection sufficient for a novel bespoke MRD assay, and are willing to provide serial whole blood specimens for ctDNA analysis. Subjects are asked to provide study specimens at baseline, pre-recurrence follow-up, and clinical recurrence (if applicable) study visits. ctDNA will be analyzed with an NGS-based MRD assay that identifies somatic genetic alterations from DNA derived from the pt’s tumor tissue, subtracts germline variants, and detects a subset of these tumor-specific (bespoke) ctDNA in the pt’s blood. The primary objective is to validate the association of post-definitive therapy and pre-recurrence follow-up ctDNA positivity with recurrence-free interval (RFI). Further objectives are to assess the: sensitivity and specificity of ctDNA positivity for subsequent clinical recurrence; contribution of post-surgery baseline, post-adjuvant therapy, and pre-recurrence follow-up ctDNA results on RFI; time from positive ctDNA to clinical recurrence in subjects who had a positive ctDNA result; and compare the Oncotype Colon Recurrence Score estimate of 3 yr recurrence risk with the observed 3 yr recurrence rate. The primary analysis will use a Cox proportional hazards regression applied to the RFI with ctDNA result (positive or negative) measured at post-surgical baseline (or end of ACT if ACT was used) and serially after that as a single, time-dependent covariate. Protocol: 16-002/NSABP C-14. Support: NSABP Foundation. Clinical trial information: 05210283.
Enabling community-led integrated women health care models for women cancers screening and early detection through EMPOWER (Enabling and Motivating Partnerships Owned by Women who Engage and Reclaim their lives) project.
Authors: Dorothy Ogada Nyongo, Jacqueline Wambua
Journal: Journal of Clinical Oncology (2022)

1541 Background: With the growing burden of Women cancers in East Africa, integrating cancer screening and prevention to optimize horizontal care delivery models is a paramount approach to strengthening women-centered and cost-effective primary healthcare. EMPOWER is a unique partnership with the government of Kenya, County referral hospitals, County First Ladies Association, International Cancer Institute, Patient organizations and Roche Kenya to demonstrate integrated cancer prevention and treatment within primary healthcare shared across the Kenyan Health system. Methods: EMPOWER clinics were launched with over 300 community health workers (including women living with disabilities) and HCPs were identified and trained to provide facility and community-based screening and early detection for breast cancer, cervical cancer, hypertension and diabetes through an integrated health systems strengthening approach. Mentorship was provided to HCPs through routinely held joint screenings and clinics, weekly Tumor Boards, Teleclinics, Telemedicine and Digital Pathology platforms. In addition, training support was provided through virtual preceptorships, skills-training workshops, hub-and-spoke oncological services provision and robust patient navigation. Results: 14 EMPOWER clinics have been launched across Kenya to increase community awareness of breast, cervical, and NCDs, strengthen capacity to deliver integrated Women cancer management services in County health clinics. In Kenya out of 25,502 people screened, 13,192 were screened for breast cancer with 97 abnormal findings identified; 10,349 screened for cervical cancer with 200 abnormal cervical screenings identified and 1,664 screened for prostate cancer with 32 abnormal findings. In addition, an integrated approach in Non Communicable Disease (NCD) care, diabetes and hypertension screening; 4,298 screened for diabetes and 6,116 screened for hypertension. All those diagnosed with cancers were linked to existing cancer care delivery systems and continuous support offered through the strengthened health care systems. Prostate cancer was added as more men turned up for screening events. Conclusions: This model is replicable and scalable across LMIC and recently the model inspired health providers’ from Tanzania and Nigeria to adopt the same for women’s cancers. EMPOWER has demonstrated a scalable care model in Kenya contributing to investments in pathology training and clinical treatment to improve challenges in referrals and updating guidelines to enable multi-disease tissue testing and handling and treatment with Standard of Care.
Shortening the baseline period in hot flash symptom control trials: Comparison of a one-day versus seven-day baseline hot flash diary.
Authors: Daniel S Childs, Paul J. Novotny, Paulina S Marrell, Kathryn Jean Ruddy, Charles L. Loprinzi
Journal: Journal of Clinical Oncology (2022)

e24094 Background: Hundreds, if not thousands, of participants are enrolled hot flash trials each year given the magnitude of the problem for breast and prostate cancer survivors. Classically, these studies have included a baseline period of 1-week, or longer, to understand the frequency and severity of hot flashes before starting a new treatment. The objective of the current study was to compare the accuracy of a 1-day baseline hot flash diary to a more traditional 1-week dairy. A shorter baseline period would be more convenient for patients and provide a more efficient study design. Methods: Raw data from 5 pilot studies and 15 phase III randomized, controlled trials (RCTs), all of which used a one-week baseline period, were obtained. Descriptive statistics were used to describe day-by-day variations in hot flash frequencies and scores, during the baseline week. Additional analyses evaluated whether the conclusions from any of the individual pilot studies would have been changed if only a 1-day baseline period had been used. For the RCTs, p-values were recalculated using mixed models, adjusting for the baseline value by including it as a covariate. Results: A total of 2,573 participants were included. On average, participants had 8.5 hot flashes per day on Day 1. Mean hot flash frequencies and scores on subsequent days (Days 2-7) were within 6% of Day 1 values. When comparing a 1-day to a 1-week baseline period, there was an absolute difference of only 0.29 hot flashes per day (SD 2.25). Re-analysis for each pilot study revealed that no individual study conclusions would have been meaningfully altered by a shorter baseline. For the RCTs, a shorter baseline period changed the results of only 1 of 24 comparisons from statistically significant to not significant, or vice versa. Conclusions: A 1-day hot flash diary appears to accurately reflect true frequency and severity of baseline hot flash symptoms in appropriately sized cohorts. Results support a shorter baseline period for pilot studies and RCTs.
Schwann cell nodal membrane disruption triggers bystander axonal degeneration in a Guillain-Barré syndrome mouse model
Authors: Rhona McGonigal, Clare I. Campbell, Jennifer A. Barrie, Denggao Yao, Madeleine E. Cunningham, Colin L. Crawford, Simon Rinaldi, Edward G. Rowan, Hugh J. Willison
Journal: Journal of Clinical Investigation (2022)

In Guillain-Barré syndrome (GBS), both axonal and demyelinating variants can be mediated by complement-fixing anti-GM1 ganglioside autoantibodies that target peripheral nerve axonal and Schwann cell (SC) membranes, respectively. Critically, the extent of axonal degeneration in both variants dictates long-term outcome. The differing pathomechanisms underlying direct axonal injury and the secondary bystander axonal degeneration following SC injury are unresolved. To investigate this, we generated glycosyltransferase-disrupted transgenic mice that express GM1 ganglioside either exclusively in neurons [GalNAcT-/--Tg(neuronal)] or glia [GalNAcT-/--Tg(glial)], thereby allowing anti-GM1 antibodies to solely target GM1 in either axonal or SC membranes, respectively. Myelinated-axon integrity in distal motor nerves was studied in transgenic mice exposed to anti-GM1 antibody and complement in ex vivo and in vivo injury paradigms. Axonal targeting induced catastrophic acute axonal disruption, as expected. When mice with GM1 in SC membranes were targeted, acute disruption of perisynaptic glia and SC membranes at nodes of Ranvier (NoRs) occurred. Following glial injury, axonal disruption at NoRs also developed subacutely, progressing to secondary axonal degeneration. These models differentiate the distinctly different axonopathic pathways under axonal and glial membrane targeting conditions, and provide insights into primary and secondary axonal injury, currently a major unsolved area in GBS research.
Characterizing online engagement and academic impact of oncology research during the COVID-19 pandemic.
Authors: Chandrasekar Muthiah, Arun Muthiah, Chapman Wei, Hina Khan
Journal: Journal of Clinical Oncology (2022)

11043 Background: There is increasing use of social media as a platform to discuss research and educate. An article’s impact can be assessed through the Altmetric Attention score (AAS), which considers the volume of social media mentions (Twitter, Facebook, Wikipedia, policy, etc), and the PlumX Impact score, which incorporates interactions on these platforms and citations. COVID-19 has encouraged novel literature in oncology, and these metrics may holistically evaluate the immediate impact of articles in addition to gradual accrual of citations. We explored the relationship between traditionally used bibliometrics (citations, impact factor) and new bibliometrics (AAS, PlumX) of the top 100 trending articles on cancer and COVID-19. Methods: The 100 articles with highest AAS featuring keywords “cancer” and “COVID-19” between March 1, 2019 and January 15, 2022 were identified via Altmetric explorer. AAS, journal, social media mentions, open access status and other characteristics were collected. Scopus database was utilized to identify PlumX scores and citation count. Analysis included Spearman correlation coefficients and ANOVA. Results: Of the 100 articles, 64% were original investigations, 18% editorials/perspectives, 6% guidelines/consensus articles and remaining article types &lt; 6% each. Original investigations comprised of 41% retrospective cohort, 33% cross-sectional, 20% prospective cohort, and remainder &lt; 4% each. Most articles were open access (91%), from cancer-focused journals (77%), and based in North America (36%); 25% were in Europe, 24% multi-continental, and remainder &lt; 8% each. Most publications were in 2020 (56%) and 2021 (40%). AAS and PlumX did not correlate with number of citations or impact factor. Open access publications were associated with greater PlumX (p = 0.033) compared to closed access; this was not seen with AAS. ANOVA showed greater AAS in Australian articles (p =.004) and greater PlumX in North American articles (p =.04). Article type or publication year did not impact AAS and PlumX. Conclusions: In our analysis, Altmetrics and PlumX did not correlate to traditional bibliometrics (citation count, impact factor) in cancer and COVID-19 articles. This suggests that these tools may be complimentary rather than predictive of citations. However, this may change given likely insufficient time for citations to accrue for 2021 studies. There were more editorials/perspective articles compared to similar studies in other specialties, suggesting greater impact of such articles in oncology during COVID-19; this is perhaps due to reliance on expert opinion given paucity of data. Additionally, we noted that PlumX benefits from open access status. Overall, as the use of social media for research dissemination grows, researchers and journal editors may employ alternative metrics to better understand ways to increase the influence of oncology literature during the pandemic.
Safety and efficacy of combined melphalan percutaneous hepatic perfusion (M-PHP) and ipilimumab plus nivolumab (IPI+NIVO) in metastasized uveal melanoma (mUM): First results of the phase Ib part of the CHOPIN trial.
Authors: Thaïs M.L. Tong, Mark C. Burgmans, Frank M. Speetjens, Arian R. van Erkel, Rutger W. van der Meer, Carla S.P. van Rijswijk, Mare A. Jonker, Inge C.F.M. Roozen, Jacob Lutjeboer, Els L. van Persijn-van Meerten, Christian H. Martini, Remco W.M. Zoethout, Fred G.J. Tijl, Christian U. Blank, Ellen Kapiteijn
Journal: Journal of Clinical Oncology (2022)

9560 Background: Uveal melanoma (UM) is the most frequent intraocular malignant tumor in adults. Approximately 50% of all patients (pts) will develop metastatic disease in the liver. Until now, there is no systemic therapy that has been shown to improve overall survival (OS), apart from tebentafusp. M-PHP is frequently applied for liver-only UM. However, the majority of pts eventually develops extrahepatic disease after M-PHP. IPI+NIVO has been shown to induce up to 20% response rates in mUM. Our observations that checkpoint inhibition was most effective on extrahepatic UM disease has led to the CHOPIN trial testing the combination of M-PHP and IPI+NIVO. Here we present the safety and efficacy data of the phase 1b part of CHOPIN. Methods: Adult pts with confirmed measurable hepatic mUM and WHO PS 0-1 were included. Two courses of 6 weekly M-PHPs (melphalan 3mg/kg, max 220mg) were combined with four courses IPI+NIVO three-weekly escalating the dosing from 1mg/kg each IPI+NIVO (cohort 1) to IPI 1mg/kg + NIVO 3mg/kg (cohort 2). Primary endpoint was safety of IPI+NIVO plus M-PHP. Secondary endpoints were best overall response (BOR) according to RECIST 1.1, progression-free survival (PFS), and OS. Results: 7 pts were included (4 male, median age 63.6 years (range 50-74)). Both cohorts were tolerated with no dose-limiting toxicities or deaths. Grade III/IV adverse events (AE) were observed in 2/3 pts in cohort 1 and in 3/4 pts in cohort 2 consisting of SIRS, febrile neutropenia, cholecystitis, neutropenia, thrombopenia, leukopenia, increased transaminases and fever. Grade I/II immune-related AEs occurred in all pts (myositis, hypothyroidism, hepatitis and dermatitis). BOR was 1 complete response, 5 partial responses and 1 stable disease accounting for an objective response rate (ORR) of 85.7%. At a median FU time of 20.2 months, 4 pts have an ongoing response. Currently the median PFS is 22.4 months, and all pts are still alive. Conclusions: Combining M-PHP with IPI+NIVO is safe at a dosing of IPI 1 mg/kg and NIVO 3 mg/kg and very promising ORR, PFS and OS have been observed. The randomized phase II part comparing M-PHP versus M-PHP+IPI+NIVO is currently recruiting. Clinical trial information: NCT04283890.
Coordinated regulation of BACH1 and mitochondrial metabolism through tumor-targeted self-assembled nanoparticles for effective triple negative breast cancer combination therapy
Authors: Xuan Yang, Yalong Wang, Junke Zhao, Hehui Rong, Yujun Chen, Mengting Xiong, Xiaoxing Ye, Shihui Yu, Haiyan Hu
Journal: Acta Pharmaceutica Sinica B (2022)

The poor prognosis of triple negative breast cancer (TNBC) results from a lack of approved targeted therapies coupled with aggressive proliferation and metastasis, which is associated with high recurrence and short overall survival. Here we developed a strategy by employing tumor-targeted self-assembled nanoparticles to coordinately regulate BACH1 (BTB domain and CNC homology 1) and mitochondrial metabolism. The BACH1 inhibitor hemin and mitochondria function inhibitor berberine derivative (BD) were used to prepare nanoparticles (BH NPs) followed by the modification of chondroitin sulfate (CS) on the surface of BH NPs to achieve tumor targeting (CS/BH NPs). CS/BH NPs were found to be able to inhibit tumor migration and invasion by significantly decreasing the amounts of tumor cell metabolites, glycolysis and metastasis-associated proteins, which were related to the inhibition of BACH1 function. Meanwhile, decreased mitochondrial membrane potential, activated caspase 3/9 and increased ROS production demonstrated coordinated regulation of BACH1 and mitochondrial metabolism. In a xenograft mice model of breast cancer, CS/BH NPs significantly inhibited tumor growth and metastasis due to the synergetic effect of hemin and BD without showing obvious toxicities for major organs. In sum, the results of efficacy and safety experiments suggest potential clinical significance of the prepared self-assembled CS/BH nanoparticles for the treatment of TNBC.